574970

research-article2015
CMSXXX10.1177/1203475415574970Journal of Cutaneous Medicine and SurgeryGupta and Lyons

Review

Journal of Cutaneous Medicine and Surgery

The Rise and Fall of Oral Ketoconazole 1­–6

© The Author(s) 2015
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DOI: 10.1177/1203475415574970
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Aditya K. Gupta1,2 and Danika C.A. Lyons2

Abstract
Background: Ketoconazole was the first broad-spectrum oral antifungal agent available to treat systemic and superficial
mycoses. Evidence of hepatotoxicity associated with its use emerged within the first few years of its approval. Growing
evidence of serious side effects including endocrine dysregulation, several drug interactions, and death led to the review of
oral ketoconazole in 2011.
Objective: This article chronicles the use of oral ketoconazole from its introduction to its near replacement in medicine.
Conclusion: Due to its hepatotoxic side effects, oral ketoconazole was withdrawn from the European and Australian
markets in 2013. The United States imposed strict relabeling requirements and restrictions for prescription, with Canada
issuing a risk communication echoing these concerns. Today, oral ketoconazole is only indicated for endemic mycoses,
where alternatives are not available or feasible. Meanwhile, topical ketoconazole is effective, safe, and widely prescribed for
superficial mycoses, particularly as the first-line treatment for tinea versicolor.

Résumé
Contexte : Le kétoconazole a été le premier antifongique oral à large spectre servant à traiter les mycoses systémique
ou superficielles. Des preuves de son hépatoxicité ont émergé dès les premières années ayant suivi son approbation.
L’accumulation de données probantes sur ses effets secondaires graves, entre autres des troubles endocriniens, plusieurs
interactions médicamenteuses et le décès, a mené à une revue de ce médicament en 2011.
Objectif : Le présent article présente les usages du kétoconazole oral, depuis son arrivée en médecine jusqu’à son
remplacement presque total.
Conclusion : En raison de ses effets secondaires hépatotoxiques, le kétoconazole oral a été retiré du marché en Europe
et en Australie en 2013. Les États-Unis ont imposé des conditions strictes relativement au nouveau libellé des indications
approuvées et des restrictions à la prescription de ce médicament, tandis que le Canada a diffusé des communiqués sur les
risques et les préoccupations soulevées par ce médicament. À l’heure actuelle, le kétoconazole oral n’est indiqué que pour
traiter les mycoses endémiques, lorsqu’il n’existe aucune autre solution. Il reste que le kétoconazole oral est efficace, sûr et
largement utilisé pour traiter les mycoses superficielles, notamment en traitement de premier recours du pityriasis versicolor.

Keywords
ketoconazole, azole antifungal, history, hepatotoxic, indication

Introduction effects.4-6 Similarly, strict restrictions and cautionary advise-

The development of the first broad-spectrum oral antifungal,
ketoconazole (Nizoral), in 1977 by Janssen Pharmaceutica
represented an exciting new advancement in the field of
medical mycology.1 Ketoconazole received United States
(US) Food and Drug Administration (FDA) clearance for use
in systemic fungal infections in July 1981.2,3 It remained the
only oral antifungal available for the treatment of systemic
fungal infections for nearly a decade thereafter.3 Until
recently, oral ketoconazole has been a mainstay of treatment
for a plethora of superficial and systemic fungal infections.
However, the drug was taken off the market in Europe and
Australia in 2013 as a result of the risk of serious hepatic side
ments were added to oral ketoconazole labelling in the US
and Canada in 2013. Today, oral ketoconazole is recom-
mended in these countries only in the event of severe or life-
threatening systemic infections when alternatives are
unavailable.7,8
1
Department of Medicine, University of Toronto, Toronto, Canada
2
Mediprobe Research Inc., London, Ontario, Canada
Corresponding Author:
Aditya K. Gupta, Mediprobe Research Inc, 645 Windermere Road,
London, ON, N5X 2P1 Canada.
Email: agupta@execulink.com
2 Journal of Cutaneous Medicine and Surgery 
Figure 1.  Timeline of major advancements in treating superficial and systemic mycoses.
A Brief Historical Overview of the
Development of Antifungals
The first known account of successful treatment of a sys-
temic mycosis was published in 1903 by de Beurmann and
Gougerot, who effectively treated a case of sporotrichosis
with potassium iodide.9,10 It was not until almost 50 years
later that the first noteworthy agent with antifungal proper-
ties, nystatin, was discovered.1,10 In 1953, the polyene
amphotericin B was developed and became the standard of
comparison for therapies for systemic mycoses.1,11
The antimicrobial properties of the most widely used anti-
fungals today, the azoles, were first described in 1944.12
These agents interfere with ergosterol biosynthesis, an essen-
tial component of the fungal cell wall, through inhibition of
the P450-dependent enzyme lanosterol 14-α-demethylase.3
In 1958, chlormidazole was the first compound specifically
developed and marketed as an antifungal. Chlormidazole’s
development renewed research interest in the field of antimi-
crobials. By 1969, developments in this field resulted in the
adoption of 3 new azole antifungals, clotrimazole, micon-
azole, and econazole, into clinical practice.10 Despite these
advancements, the field of dermatology still lacked a broad-
spectrum antifungal agent (Figure 1).
The Rise of Ketoconazole
Ketoconazole, a broad-spectrum imidazole antifungal, was
introduced in 1977 and received FDA approval in 1981.13,14
At the time of its approval, ketoconazole’s broad-spectrum
activity presented clear advantages over established antimy-
cotics in that it combined efficacy similar to miconazole with
oral absorption akin to griseofulvin.15-17 Like other imidazole
compounds, ketoconazole interferes with ergosterol biosyn-
thesis through inhibition of a P450-dependent enzyme,
ultimately altering the structure and function of the cell
wall.14,18 Early in vitro studies demonstrated ketoconazole’s
activity against dermatophytes,13,16,19,20 yeasts,13,16,19,20
molds,19 and dimorphic fungi20 as well as some bacteria.19
Ketoconazole also demonstrated in vivo activity in animal
models of oral and vaginal candidosis,19,21 cutaneous candi-
dosis,19,20 and systemic candidosis.20
Multiple small clinical studies demonstrated the efficacy
of oral ketoconazole as treatment for both systemic and
superficial mycoses caused by yeasts and fungi, including
dermatophytes (reviewed in Heel et al21). At the time, the
drug appeared to be well tolerated with most adverse effects
occurring in <1% of study participants. Nausea and vomiting
(3%), pruritus (1.7%), and abdominal pain (1.3%) were the
most frequently reported adverse side effects.21 The versatil-
ity of oral ketoconazole led to its recognition as the most
effective and most extensively prescribed oral azole antifun-
gal of its time.3 It was also included in the World Health
Organizations (WHO) Model List of Essential Medicines for
many years.22 However, concern over much more serious
adverse reactions to oral ketoconazole soon came to the
forefront.6
The Descent of Oral Ketoconazole
The descent of oral ketoconazole began with the acknowl-
edgment of symptomatic and asymptomatic hepatotoxicity
associated with its use.23 Evidence soon followed that sug-
gested that ketoconazole may not only cause liver injury but
also interfere with endocrine regulation.24,25 Finally, the
potential for drug-drug interactions became apparent, as oral
ketoconazole was found to alter the metabolism of concomi-
tant medications via its effect on CYP3A enzymes.26-28
By the early 1980s, it was apparent that oral ketoconazole
was associated with hepatic injury. In 1983, Janssen and
Gupta and Lyons 3
Symoens23 conducted an analysis of the incidence of symp-
tomatic and asymptomatic (elevated liver enzymes with no
clinical signs or symptoms) hepatic reactions to ketocon-
azole reported worldwide from March 1981 to March 1982.
The report suggested that hepatic abnormalities manifested
most often as asymptomatic increases in liver enzyme levels.
These abnormalities were transient, normalizing throughout
the duration of treatment or following cessation of treatment.
The report described 31 incidences of symptomatic hepatic
reactions to oral ketoconazole. All symptomatic patients made
a full recovery with the exception of 1 patient who died of
hepatic necrosis.23 A subsequent addendum to the publication
described an additional 46 cases of symptomatic hepatic reac-
tions to oral ketoconazole and an additional death by September
1982.23 The authors estimated that 0.008% (1:12 000) of
patients administered oral ketoconazole may suffer symp-
tomatic hepatic side effects. Subsequent estimations of the
incidence rate of symptomatic ketoconazole-induced liver
injury ranged from 0.007% (1:15 000)29 to as high as 0.05%
(1:2000)30 and 0.2% (1:500).31
The recognition of ketoconazole-associated hepatotoxic-
ity among scientists, physicians, and the general public led to
debate regarding the proper prescription of oral ketoconazole
and indications for the timing of treatment termination. For
instance, in 1983, the Wall Street Journal described the out-
rage and discontent of a local consumer advocacy organiza-
tion, the Public Citizen’s Health Research Group (PCHRG),
regarding ketoconazole.32 The PCHRG was petitioning the
FDA for additional warnings of hepatotoxicity on ketocon-
azole packaging and cautioning physicians against off-label
prescription of the drug for superficial mycoses. The group
accused the FDA of failing to acknowledge the extent of the
liver damage that ketoconazole had caused.32 A representa-
tive of the FDA assured the public that the package labelling
of ketoconazole would be revised to include mention that 1
in every 10 000 patients may suffer often reversible, but
sometimes fatal, liver damage.32
In the scientific community, some argued that asymptom-
atic increases in liver enzyme levels were fleeting and did not
warrant drug cessation unless clinical signs of liver injury
developed.33 Others argued that elevated liver enzyme levels
were extremely serious and warranted treatment cessation once
levels 3 times the upper limit of normal were reached, regard-
less of whether or not patients were symptomatic.34,35 Bernuau
et al35 noted that 3 incidences of sudden hepatic failure occurred
after treatment termination was delayed in spite of elevated
liver enzymes. Furthermore, the incidence of acute liver injury
associated with oral ketoconazole use was determined to be
higher than any of the other oral antifungal medications.31 A
meta-analysis of studies from 1979 to 2012 calculated the inci-
dence of oral ketoconazole-associated hepatotoxicity to range
from 3.6% (95% CI, 3.2-4.2) to 4.2% (95% CI, 3.7-4.9) and to
be unrelated to dose and duration of treatment.36
Endocrine dysregulation as a result of oral ketoconazole
administration can lead to decreased testosterone production,
decreased libido, gynecomastia, and oligospermia. By 1982,
6 incidences of gynecomastia following ketoconazole treat-
ment were documented.24,37 Subsequent in vitro investiga-
tions revealed that ketoconazole inhibits testosterone
synthesis38,39 and adrenal steroidogenesis.38 Ketoconazole
was thought to achieve its effects on testosterone synthesis
and adrenal steroidogenesis through interference with P450-
dependent enzymes.40,41 It became clear that the activity of
ketoconazole is not specific to P450-dependent fungal
enzymes; rather, it may affect any mammalian P450-
dependent enzyme, potentially leading to unforeseen inci-
dences of adverse reaction or toxicity.
Oral ketoconazole was also found to increase the risk of
drug interactions as it is a potent inhibitor of the CYP3A4
enzyme.18 Therefore, co-administration with any agent that
inhibits CYP3A4 may increase the bioavailability of keto-
conazole and thereby increase the therapeutic and/or adverse
effects of the drug.18 Similarly, co-administration of ketocon-
azole with any other drug metabolized by CYP3A4 may
increase the blood plasma levels of that agent and prolong its
effects.42,43 Conversely, agents that decrease gastric acidity
or induce CYP3A4 may decrease the bioavailability and
therapeutic effect of ketoconazole.44-47 As a result, many
medications are contraindicated with ketoconazole, while
others are simply not recommended or advised to be used
with caution.18
Ketoconazole Under Review:
New Restrictions and Regulations
Worldwide
The use of oral ketoconazole was suspended in France in
July 2011 after a review performed by the National Agency
for the Safety of Medicine and Health Products (ANSM)
deemed that its risks outweighed its therapeutic benefits.4
This suspension triggered an EU-wide evaluation. Two years
later, the European Medicines Agency (EMA) released a
statement announcing the Committee on Medicinal Products
for Human Use’s (CHMP) recommendation that oral keto-
conazole’s marketing authorizations be suspended.4
Additionally, the Australian government announced that oral
ketoconazole would be deregistered and discontinued as of
December 1, 2013.5 Again, the risks of serious hepatotoxic-
ity associated with oral ketoconazole use were believed to be
higher than the benefits of its therapeutic effects.
In July 2013, the US FDA announced their amendments to
oral ketoconazole product labelling and warned against the
use of oral ketoconazole as a first line of treatment. The new
product monographs included a strong recommendation
against the use of ketoconazole in patients with liver disease
and introduced new recommendations for assessing and mon-
itoring liver function. Recommended testing prior to treat-
ment includes baseline alanine aminotransferase (ALT),
aspartate aminotransferase (AST), total bilirubin, alkaline
phosphatase, prothrombin time, and international normalized
4 Journal of Cutaneous Medicine and Surgery 
Table 1.  Summary of Worldwide Oral Ketoconazole Guidelines.a
Canada (Health Canada)
Indications Serious or life-threatening
systemic fungal infections
when other options not
available or tolerated
Monitoring Liver function tests before
treatment, at weeks 2 and 4,
monthly thereafter.
Criteria to interrupt use Elevated liver parameters
(>3 times normal) or if
clinical signs/symptoms liver
disease develop
a
Symptoms of liver dysfunction include anorexia, nausea, vomiting, jaundice, abdominal pain, dark urine, or pale stool. ALT, alanine aminotransferase;
EMA, European Medicines Agency; FDA, Food and Drug Administration; NPS, National Prescribing Service
ratio (INR).8 The FDA recommended that oral ketoconazole
be prescribed solely for endemic mycoses and only when a
suitable alternative is unavailable. Also, it is cautioned that
current medications should be assessed for possible interac-
tions with ketoconazole before it is prescribed.8
Within the same year, Health Canada released a risk com-
munication endorsing amendments to oral ketoconazole’s
product monograph.7 The label now emphasizes the risk of
hepatotoxicity and the need for liver function monitoring
even when prescribed at the recommended dose and in
patients with no preexisting liver abnormalities or serious
medical conditions.7 As in the US, indications were revised
such that oral ketoconazole is to be prescribed only for seri-
ous or life-threatening systemic fungal infections and never
prescribed to individuals with existing liver disease. The new
restrictions and recommendations for North America and
Europe are summarized in Table 1.
Conclusion
In 1977, the introduction of ketoconazole represented an
exciting new advancement in the field of medical mycology.
Few effective therapeutic options to treat systemic mycoses
were available at the time, and the development of new
agents was at a near standstill. The therapeutic efficacy of
ketoconazole against a wide range of fungi, dimorphic fungi,
and yeasts led to widespread use in patients with superficial
and systemic mycoses. Ketoconazole was heralded for many
years as the only drug of its kind. Oral ketoconazole use
would eventually wane as more evidence of hepatotoxicity,
endocrine dysregulation, and drug interactions emerged.
After over 30 years in clinical practice, the serious hepato-
toxic risks posed by the drug6 and the availability of less
toxic alternatives led to revocation of marketing authoriza-
tion in Europe and Australia,4,5 the imposition of strict
USA (FDA) EU (EMA) Australia (NPS)
Serious or life-threatening No longer prescribed Deregistered,
systemic fungal infections discontinued
when other options not
available or tolerated (not for
skin or nails)
Liver function tests before  
treatment, serum ALT
monitored weekly, adrenal
function monitored in select
patients.
ALT at upper limit of normal  
or 30% above baseline, or if
symptoms of abnormal liver
function
prescription regulations in the US,8 and endorsement of this
new safety information by Health Canada.7
The decrease in popularity of oral ketoconazole for treat-
ment of systemic mycoses has not left a gap in medical treat-
ment. First- and second-generation triazoles with fewer
safety concerns are effective treatment options for systemic
mycoses (Figure 1).48-50 Ketoconazole itself has not disap-
peared from use in medical practice. Topical ketoconazole
does not reach the systemic circulation and is a safe and
effective therapy for dermatological conditions.51 Topical
formulations of ketoconazole cream, shampoo, and foam are
particularly effective in treating superficial mycoses caused
by Malassezia species. Topical ketoconazole serves as the
first-line treatment for tinea versicolor and is also used
in treating seborrheic dermatitis and Malassezia
folliculitis.52,53
Today, oral ketoconazole is now only recommended as a
second line of treatment for the most severe systemic myco-
ses when viable alternatives are unavailable. Despite its fate,
oral ketoconazole represented the beginning of a new era of
research and development of antimycotic agents, without
which, the treatment options for superficial and systemic
mycoses that we have today would not exist (Figure 1).
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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